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Characterization Of Ss Arrestins Trafficking And Signaling Functions On G Protein Coupled Receptors
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Book Synopsis Characterization of [beta]-arrestins Trafficking and Signaling Functions on G Protein-coupled Receptors by : Etienne Khoury
Download or read book Characterization of [beta]-arrestins Trafficking and Signaling Functions on G Protein-coupled Receptors written by Etienne Khoury and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Characterization of ß-arrestins Trafficking and Signaling Functions on G Protein-coupled Receptors by : Etienne Khoury
Download or read book Characterization of ß-arrestins Trafficking and Signaling Functions on G Protein-coupled Receptors written by Etienne Khoury and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The heptahelical G protein-coupled receptors (GPCRs) are the largest, most versatile superfamily of cell surface receptors and constitute the most common target for many therapeutic drugs. They participate in various physiological processes via signaling transduction, mainly induced by heterotrimeric G proteins. Following activation, these 7-transmembrane receptors recruit [beta]-arrestin for endocytosis. Beta-arrestins will directlyassociate GPCRs to several components of the endocytic machinery, such as clathrin and adaptor protein 2 (AP-2), allowing the receptor to internalize. Over the years, [beta]-arrestins were shown to also act as signaling adaptors upon binding to agonist-occupied GPCRs; however, the mechanism regulating receptor/[beta]-arrestin complexes in endosomes was not yet addressed. Based on a previous study where we showed that [beta]-arrestin serves as a scaffolding protein for several signaling effectors (e.g. MAPK) in the endosomes, we hypothesized that endosomal MAPK activity would be necessary to maintain the GPCR/[beta]-arrestin-2 complex, thus regulating receptor trafficking. Our first study revealed a putative phosphorylating MAPK motif (Thr178) in [beta]-arrestin-2 suggesting that endosomal MAPK activity is involved in such process. Using biochemical assays and FRAP (Fluorescence Recovery After Photobleaching) approach to assess the life-time of bradykinin B2 receptor (B2R)/[beta]-arrestin-2 endosomal complexes, we showed that the MAPK putative site in [beta]-arrestin-2 is involved in regulating the association between the arrestin and its receptor. The role of [beta]-arrestin-2 'hinge' domain was tested for such effect, and using arrestin mutants demonstrated distinct behaviours between [beta]-arrestin-2 species on GPCRs trafficking and agonist mediated receptor signaling. This study highlights a strong correlation between MAPKsignaling and the regulation of endosomal GPCR/[beta]-arrestin-2 interactions. In addition to the 'hinge' domain, structural studies showed that the polar core, as well as the arrestins loops, were also crucial for [beta]-arrestin activation. Based on the crystal structure of [beta]-arrestin-1, a virtual screen was then conducted in order to identify aselective pharmacological inhibitor of [beta]-arrestin-2. Results showed a unique compound, namely UM0012685 which firstly, blocked V2-vasopressin receptor (V2R) endocytosis; Secondly, inhibited [beta]-arrestin recruitment; Thirdly, decreased the stability of the receptor and [beta]-arrestin-2 endosomal complexes and finally inhibited [beta]-arrestin-2-dependent MAPK activation upon agonist stimulation of the V2R. This compound was also used as a tool to determine [beta]-arrestins trafficking function on [beta]2-adrenergic receptor ([beta]2AR) recycling. These results uncover a better understanding of the underlying mechanism regulating [beta]-arrestin in the endosomes as well as the intracellular trafficking modulation of GPCRs. Our findings also reveal a useful tool to investigate the multifunctional aspect of [beta]-arrestins in the cell." --
Download or read book G Protein-Coupled Receptors written by and published by Academic Press. This book was released on 2016-02-26 with total page 522 pages. Available in PDF, EPUB and Kindle. Book excerpt: G-Protein-Coupled Receptors: Signaling, Trafficking, and Regulation, a new volume in the Methods in Cell Biology series continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers research methods in G-Protein-Coupled Receptors, and includes sections on such topics signaling, trafficking and regulation. - Covers the increasingly appreciated cell biology field of G-protein-coupled receptors - Includes both established and new technologies - Contributed by experts in the field - Covers topics such as signaling, trafficking, and regulation
Download or read book G Protein-Coupled Receptors written by and published by Academic Press. This book was released on 2019-01-05 with total page 332 pages. Available in PDF, EPUB and Kindle. Book excerpt: G-Protein-Coupled Receptors, Part B, 2nd Edition, Volume 149, the latest release in the Methods in Cell Biology series, continues the legacy of this premier serial with quality chapters authored by leaders in the field. This volume covers Optical Approaches for Visualization of Arrestin Binding to Muscarinic Receptors, Luciferase Reporter Assay for Unlocking Ligand-mediated Signaling of GPCRs, Assays to Measure GPCR Dependent Cellular Migration, Characterization of the Frizzled GPCRs, Binding Assays for Bradykinin and Angiotensin Receptors, Detection of Misfolded Rhodopsin Aggregates in Cells, Measuring GPCR Ubiquitination and Trafficking, Culture of Primary Neurons and its Use in Studying GPCR Trafficking, and much more. Covers the increasingly appreciated cell biology field of G-protein-coupled receptors Includes both established and new technologies Contributed by experts in the field
Book Synopsis Nuclear G-Protein Coupled Receptors by : Bruce G. Allen
Download or read book Nuclear G-Protein Coupled Receptors written by Bruce G. Allen and published by Humana. This book was released on 2016-08-23 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Nuclear G-Protein Coupled Receptors: Methods and Protocols is a compilation of a number of conceptual and methodological aspects important for the validation and characterization of intacrine signaling systems. To date, the best-characterized intracrine signaling system is that of angiotensin II (Ang II), covered in depth in various chapters. Methodology to study the subcellular localization and function of GPCRs and other signaling systems is provided, as well as numerous chapters focusing on methods designed to understand signaling mediated by nuclear and other internal GPCRs. Methods are also described to study the formation of second messengers such as cAMP and to study the trafficking of receptors from the cell surface. Written in the successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and easily accessible, Nuclear G-Protein Coupled Receptors: Methods and Protocols seeks to serve both professionals and novices with state-of-the-art approaches to characterize what is becoming a common theme in cellular signaling.
Book Synopsis Methods for the Discovery and Characterization of G Protein-Coupled Receptors by : Craig W. Stevens
Download or read book Methods for the Discovery and Characterization of G Protein-Coupled Receptors written by Craig W. Stevens and published by Humana Press. This book was released on 2011-07-15 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The goal of the characterization and discovery of G protein-coupled receptors, arguably the most important class of signaling molecules in humans and other vertebrates, has spawned numerous vital methodologies. In Methods for the Discovery and Characterization of G Protein-Coupled Receptors, experts in the field present the very latest on the methods and technology used to characterize and discover novel mechanisms of GPCRs which, in many cases, can be used directly to design experiments for the reader’s particular GPCR of interest and their specific avenue of investigation. Divided into four convenient sections, this detailed volume covers GPCRs in the genome, trafficking of GPCRs, GPCRs on the membrane, as well as the regulation of these key receptors. Chapters also feature an important section called “Future Directions” which gives the reader an insight into advances soon to be realized in each area. Written for the popular Neuromethods series, this book contains the kind of detailed description and implementation advice that is crucial for getting optimal results. Authoritative and cutting-edge, Methods for the Discovery and Characterization of G Protein-Coupled Receptors serves as an ideal guide for scientists determined to further our knowledge of crucially important set of receptors.
Book Synopsis Characterization of Protease-activated Receptor-4 Trafficking and Heterodimerization in Modulating Receptor Signaling by : Thomas Horace Smith
Download or read book Characterization of Protease-activated Receptor-4 Trafficking and Heterodimerization in Modulating Receptor Signaling written by Thomas Horace Smith and published by . This book was released on 2016 with total page 140 pages. Available in PDF, EPUB and Kindle. Book excerpt: G protein-coupled receptors (GPCRs) are transmembrane proteins that allow cells to respond to extracellular stimuli. GPCR activation occurs when a ligand binds to the extracellular portion of the receptor. The ligand-bound receptor undergoes a conformational change that allows the intracellular domain of the receptor to engage and activate signaling effectors. The protease-activated receptors (PARs) are a family of GPCRs that are activated by proteases such as thrombin. Unlike traditional GPCRs, which can return to their inactive state after signaling, PARs are irreversibly activated. Therefore, the eventual fate of an activated PAR is degradation. The internalization and endocytic sorting of PARs play key roles in their signal regulation. Trafficking has been well-characterized for PAR1, the prototypical thrombin receptor. PAR4 was the last of the four thrombin receptor to be discovered, and has in large part been relatively under-studied. Recent studies have shown that PAR4 plays distinct roles that differ from those of PAR1, and as such may represent a potential drug target. Thus, understanding the mechanisms that regulate PAR4 signal regulation is important. In this dissertation, I characterized the role that trafficking and heterodimerization play in regulating PAR4 signaling. I found that adaptor-protein complex-2 (AP-2) is a key mediator of PAR4 agonist-induced internalization, and that AP-2 binds to intracellular loop 3 (ICL3) of PAR4. Disruption of PAR4 internalization resulted in enhanced and prolonged ERK1/2 activation, suggesting that endocytosis may mediate PAR4 signal attenuation. I also characterized the role of heterodimerization with the puringeric receptor P2Y12 in modulating PAR4 signaling. Previous studies had demonstrated that PAR4 and P2Y12 coordinate [beta]-arrestin-dependent Akt activation. My work strongly suggests that PAR4 and P2Y12 physically associate basally and co-internalize in response to activation of PAR4. I also demonstrate that [beta]-arrestin is recruited to the co-internalized PAR4-P2Y12 complex. In contrast to the effect on ERK1/2 activation, disruption of PAR4 internalization diminished Akt activation. Taken together, the studies summarized in this dissertation highlight the importance of PAR4 internalization in modulating activity of functionally and spatially distinct signaling pathways.
Book Synopsis The G Protein-Coupled Receptors Handbook by : Lakshmi A. Devi
Download or read book The G Protein-Coupled Receptors Handbook written by Lakshmi A. Devi and published by Springer Science & Business Media. This book was released on 2008-03-01 with total page 414 pages. Available in PDF, EPUB and Kindle. Book excerpt: A comprehensive survey of the many recent advances in the field of G protein-coupled receptors (GPCR). The authors describe the current knowledge of GPCR receptor structure and function, the different mechanisms involved in the regulation of GPCR function, and the role of pharmacological chaperones in GPCR folding and maturation. They also present new findings about how GPCR dimerization/oligomerization modifies the properties of individual receptors and show how recent developments are leading to significant advances in drug discovery, such as the detection of ligands for orphan GPCRs. Also discussed are the most recent developments that could lead to new drug discoveries: the role of GPCRs in mediating pain, the development of receptor-type selective drugs based on the structural plasticity of receptor activation, and the identification of natural ligands of orphan GPCRs (deorphanization) as possible drug targets.
Book Synopsis Regulation of G Protein Coupled Receptor Function and Expression by : Jeffrey L. Benovic
Download or read book Regulation of G Protein Coupled Receptor Function and Expression written by Jeffrey L. Benovic and published by Wiley-Liss. This book was released on 1999-11-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recent advances in molecular and cell biology enabling the cloning, expression, and mutagenesis of signal transduction proteins has prompted an explosion of knowledge in the field of receptor regulation, facilitating the discovery of new classes of regulatory proteins, and providing a basis and means for manipulating receptor function through multiple intracellular targets. This volume covers methods used to examine how the function(s) of receptors are regulated. Understanding how to regulate the function and expression of these receptors is critical in determining how to modify receptors and to translocating receptors away from the cell surface and its recycling. Individual chapters focus on specific techniques used to characterize receptors (epitope tagging, measurement and analysis of receptor phosphorylation, analysis of the kinetics of receptor desensitization, and assessment of receptor/G protein coupling); the role of regulatory proteins (receptor kinases and phosphatases, arrestins) in modulating receptor function; and the methods used to measure receptor trafficking (ligand binding, immunofluoresence) and expression (transcriptional and translational regulation). * Covers a broad range of important concepts and methodologies which are current in the study of G protein-coupled receptors (GPCRs) * G-protein coupled receptors make up over 40% of the current pharmacological targets * Provides detailed protocols for executing various strategies and offers informed judgments as to what approaches are and aren't useful * Volume Editor, Jeffrey Benovic, is a dominant world leader in the study of receptor regulation of GPCR kinases and is highly respected in the field
Book Synopsis Functional Characterization of Protease-activated Receptor-1 Palmitoylation in Receptor Signaling and Trafficking by : Isabel Canto Cordova
Download or read book Functional Characterization of Protease-activated Receptor-1 Palmitoylation in Receptor Signaling and Trafficking written by Isabel Canto Cordova and published by . This book was released on 2014 with total page 172 pages. Available in PDF, EPUB and Kindle. Book excerpt: G protein-coupled receptors (GPCRs) are the largest family of signaling receptors that respond to diverse stimuli and regulate many physiological responses. GPCRs elicit their cellular responses by coupling to distinct subtypes of heterotrimeric G-proteins composed of G[alpha] and G[beta][gamma] subunits. Activated GPCRs undergo conformational changes that allow the receptor to exchange GDP for GTP on the G[alpha] subunit, which induces dissociation from the [beta][gamma] subunits and subsequent downstream signaling. Protease-activated receptor-1 (PAR1) is a member of a family of GPCRs that are proteolytically activated. PAR1 is a receptor for the coagulant protease thrombin, and is capable of coupling to multiple G-protein subtypes to elicit various cellular responses; however, the mechanisms that regulate this selectivity are not well understood. Palmitoylation is a post-translational modification that many GPCRs possess, and is defined as the addition of palmitate, a 16 carbon fatty acid, to a cysteine residue via a thioester linkage. Many GPCRs are palmitoylated on their C-terminal tails, but the role of this modification differs based on the GPCR being examined. In this dissertation, I examined the role of palmitoylation in PAR1 signaling and trafficking. I defined the sites of PAR1 palmitoylation to occur on conserved C-tail cysteine residues C387 and C388. I discovered that palmitoylation is important for other PAR1 post-translational modifications, specifically phosphorylation and ubiquitination. I also show that palmitoylation of PAR1 regulates the accessibility of a nearby tyrosine-based sorting motif to the adaptor-protein complex-2 (AP-2) and -3 (AP-3), which controls receptor internalization and degradation. Additionally, palmitoylation appears to be important for the regulation of selective PAR1-induced signaling pathways such as G[alpha]12/13 -induced RhoA activation, G[alpha]i coupling, and thrombin-stimulated p38 MAPK signaling pathways. However, thrombin-induced G[alpha]q-mediated phosphoinositide hydrolysis and ERK1/2 activation are unperturbed in the absence of PAR1 palmitoylation. Taken together, the studies summarized in this dissertation highlight the relevance of palmitoylation for PAR1 function, and suggest that palmitoylation governs a C-tail conformation that is important for accessibility of other proteins such as ligases, kinases, adaptor proteins, and G-proteins, ultimately regulating PAR1 signaling and trafficking.
Download or read book G Protein Coupled Receptors written by and published by Academic Press. This book was released on 2013-01-24 with total page 489 pages. Available in PDF, EPUB and Kindle. Book excerpt: This new volume of Methods in Enzymology continues the legacy of this premier serial by containing quality chapters authored by leaders in the field. This volume covers G protein coupled receptors and includes chapters on such topics as G protein-coupled receptor trafficking motifs, structure-based virtual screening, and automation-friendly high throughput assays for identification of pharmacoperone drugs. - Continues the legacy of this premier serial with quality chapters authored by leaders in the field - Covers G protein coupled receptors - Contains chapters on such topics as G protein-coupled receptor trafficking motifs, structure-based virtual screening, and automation-friendly high-throughput assays for identifying pharmacoperone drugs
Book Synopsis The Structural Basis of Arrestin Functions by : Vsevolod V. Gurevich
Download or read book The Structural Basis of Arrestin Functions written by Vsevolod V. Gurevich and published by Springer. This book was released on 2017-05-24 with total page 302 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume summarizes our current understanding of the structural basis of the functions of arrestin family of proteins. Arrestins were first discovered as key players in the desensitization of G protein-coupled receptors (GPCRs). Recent studies showed that arrestins are important signal transducers in their own right, organizing multi-protein complexes and scaffolding numerous signaling cascades that regulate cell proliferation, differentiation, and apoptotic death. Here arrestin functions are described primarily from the structural prospective. The book covers basal structure of arrestin proteins, receptor binding-induced conformational changes in arrestins, as well as the structure of “pre-activated” mutants. Particular focus is on the arrestin elements interacting with numerous binding partners, GPCRs and cytoplasmic signaling proteins. We expect that this information and insights will help to understand and exploit the phenomenon of signaling bias, which is a new promising direction in drug discovery. The chapters are written by the world-class specialists in the field, mostly the people who actually contributed the data discussed. The book gives coherent historical prospective and describes the most recent findings. The book would be particularly useful for scientists in academia and industry working in the fields of pharmacology, cell biology, structural biology, and drug discovery. We expect that the focus on the molecular basis of protein-protein interactions would help to develop novel tools for engaging this important type of targets for research and therapeutic purposes.
Book Synopsis Characterization of an Orphan G Protein-coupled Receptor by : Li Zhang
Download or read book Characterization of an Orphan G Protein-coupled Receptor written by Li Zhang and published by . This book was released on 2009 with total page 152 pages. Available in PDF, EPUB and Kindle. Book excerpt: Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor (GPCR) in the mammalian bombesin receptor family. Despite great difficulties imposed by the missing endogenous ligand, this study used three different approaches to investigate the functions of BRS-3: pharmacological characterization of a synthetic BRS-3 agonist (Chapter 1); anatomical characterization of BRS-3 mRNA expression in the rodent central nervous system (Chapter 2); and behavioral characterization of BRS-3 deficient mice (Chapter 3). Synthetic compound 16a was identified as a potent and selective agonist for BRS-3 and a potential tool to study BRS-3 activation in vitro and possibly in vivo. Compound 16a activation of BRS-3 was found to promote beta-arrestin translocation to the cell membrane and no receptor internalization was observed in receptor trafficking studies. To reveal the anatomical substrates mediating BRS-3's biological actions, BRS-3 mRNA expression in the rodent CNS was investigated by in situ hybridization. BRS-3 mRNA was found in a wide variety of brain regions, with highest expression in the hypothalamus. Neurochemical characteristics of BRS-3-expressing neurons were investigated by identifying potential neurotransmitters or neuropeptides co-produced with BRS-3. A large number of BRS-3-expressing neurons were found to be glutamatergic and BRS-3 mRNA partially co-localizes with corticotropin-releasing factor (CRF) and growth hormone-releasing hormone (GHRH), suggesting interaction with feeding and growth-related endocrine systems. The prominent expression of BRS-3 in the hypothalamus supports a possible involvement of BRS-3 signaling in regulating energy homeostasis, while BRS-3 expression in the paraventricular hypothalamic nucleus, amygdala and lateral parabrachial nucleus indicates a role in modulating anxiety and stress. In Chapter 3, BRS-3 deficient mice were used to evaluate the impact of BRS-3 deficiency on high-fat diet induced metabolic changes and on the regulation of anxiety-like and depressive-like behaviors in stressful situations, such as in the light-dark box test, the forced-swim test and the tail suspension test. BRS-3 deficient mice were more susceptible to diet-induced obesity, supporting the hypothesis that BRS-3 may be involved in energy metabolism, especially through the leptin signaling pathway. The attenuated emotional responses of BRS-3 deficient mice in stressful situations suggest that BRS-3 may modulate stress response, potentially through CRF-mediated activation of the HPA axis.
Book Synopsis Molecular Aspects of G Protein-coupled Receptors by : Francisco Ciruela
Download or read book Molecular Aspects of G Protein-coupled Receptors written by Francisco Ciruela and published by Nova Publishers. This book was released on 2008 with total page 328 pages. Available in PDF, EPUB and Kindle. Book excerpt: In the recent years, studies based on two-hybrid screens, proteomic, biochemical and cell biology approaches, have shown that intracellular domains of G protein-coupled receptors (GPCR) or heptaspanning membrane receptors (HSMRs) interact with intracellular proteins. These interactions are the basis of a protein network associated to these receptors which includes scaffolding proteins containing one or several PDZ (post-synaptic density-95, discs large, zona occludens-1) domains, signalling proteins and proteins of the cytoskeleton. The present book is focused on the emerging evidence for interactions of G protein-coupled receptors with scaffolding, cytoskeletal and signalling proteins that will play a role in the targeting, anchoring and functioning of these receptors in the plasma membrane, thus contributing to cell development and plasticity.
Book Synopsis Receptor-Receptor Interactions by : Kjell Fuxe
Download or read book Receptor-Receptor Interactions written by Kjell Fuxe and published by Springer Science & Business Media. This book was released on 2013-03-13 with total page 577 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Principles of Endocrinology and Hormone Action by : Antonino Belfiore
Download or read book Principles of Endocrinology and Hormone Action written by Antonino Belfiore and published by Springer. This book was released on 2018-02-08 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume provides comprehensive coverage of the current knowledge of the physiology of the endocrine system and hormone synthesis and release, transport, and action at the molecular and cellular levels. It presents essential as well as in-depth information of value to both medical students and specialists in Endocrinology, Gynecology, Pediatrics, and Internal Medicine. Although it is well established that the endocrine system regulates essential functions involved in growth, reproduction, and homeostasis, it is increasingly being recognized that this complex regulatory system comprises not only hormones secreted by the classic endocrine glands but also hormones and regulatory factors produced by many organs, and involves extensive crosstalk with the neural and immune system. At the same time, our knowledge of the molecular basis of hormone action has greatly improved. Understanding this complexity of endocrine physiology is crucial to prevent endocrine disorders, to improve the sensitivity of our diagnostic tools, and to provide the rationale for pharmacological, immunological, or genetic interventions. It is such understanding that this book is designed to foster.
Download or read book GPCR Signaling in Cancer written by and published by Academic Press. This book was released on 2020-03-06 with total page 164 pages. Available in PDF, EPUB and Kindle. Book excerpt: GPCR Signaling in Cancer, Volume 145, the latest release in the Advances in Cancer Research series, highlights recent developments in the area of GPCRs and cancer biology. Chapters included in this volume cover several GPCRs and their downstream effectors as case examples to highlight their fundamental understanding and therapeutic potential. Specific chapters address the Role of GRKs and beta-arrestins in cancer, Atypical GPCRs in cancer, the Role of a chemokine receptor (CCR) 5 in cancer, Targeting G protein-coupled receptors for therapeutics in cancer, Emerging GPCR signaling pathways in cancer, and more. G protein-coupled receptors (GPCRs) constitute a large family of cell surface receptors which are involved in nearly every cellular and physiological event. These receptors can recognize a broad array of ligands and they are targeted by nearly one third of the currently prescribed drugs including anti-cancer therapeutics. Covers the latest concepts in GPCR signaling and their relevancy to cancer biology Presents new indications for anti-cancer therapeutic programs Includes sections on cross-talk and signaling networks of GPCRs and effectors in molecular oncology and therapeutics
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